Slideshare uses cookies to improve functionality and performance, and to provide you with relevant advertising. If you continue browsing the site, you agree to the use of cookies on this website. See our User Agreement and Privacy Policy.

Slideshare uses cookies to improve functionality and performance, and to provide you with relevant advertising. If you continue browsing the site, you agree to the use of cookies on this website. See our Privacy Policy and User Agreement for details.

72.
Che cosa è il concetto di massa
farmacocinetica
• we described a non-linear dosing weight adjustment
(pharmacokinetic mass), which proposes that the dose of
fentanyl should be determined per kg of pharmacokinetic mass,
rather than TBW. The relationship between pharmacokinetic
mass and TBW is non-linear, and is shown as a nomogram
• clearance was also measured in the previous study, and it had
a similar non-linear relationship to TBW (Appendix Fig. A1B).
Our previous findings suggested that pharmacokinetic mass is
the dosing weight for fentanyl that reflects
• the influence of TBW on clearance. The least-squares fit for this
relationship indicates a dose of 1.22 microg h1 per unit of
pharmacokinetic mass – 7.5.
• If the relationship is forced through the origin, the sums of
squares of deviations from linear regression is only increased
by 0.7%, and the dose for postoperative analgesia is 1.12 mg
h1 (or simply 1.1 mg h1) per unit of pharmacokinetic mass.

73.
(A) Nomogram for the relationship between analgesic dosing
weight for fentanyl, i.e. pharmacokinetic mass (PK mass),
and total body weight (TBW). (B) Nomogram for the
relationship between total body clearance of fentanyl (ml
min1) and total body weight (TBW
).

74.
Pharmacokinetic mass (PK) weights for selected total body
weights.PK mass is calculated from the formula: PK
mass=52/[1+(196.4·e0.025 TBW– 53.66)/100], as described in
reference 2. The data are rounded to whole numbers
for convenience; rounding errors are <1% in all cases. TBW,
total body weight; PK mass, pharmacokinetic mass

77.
Minto CF,Schnider TW, Shafer SL.Pharmacokinetics
and Pharmacodynamics of Remifentanil II. Model
Application .Anesthesiology 86:24-33, 1997
•
•
•
•
* Background: The pharmacokinetics and pharmacodynamics of remifentanil were studied in 65 healthy volunteers using
the electroencephalogram (EEG) to measure the opioid effect. In a companion article, the authors developed complex
population pharmacokinetic and pharmacodynamic models that incorporated age and lean body mass (LBM) as significant
covariates and characterized intersubject pharmacokinetic and pharmacodynamic variability. In the present article, the
authors determined whether remifentanil dosing should be adjusted according to age and LBM, or whether these covariate
effects were overshadowed by the interindividual variability present in the pharmacokinetics and pharmacodynamics.
Methods: Based on the typical pharmacokinetic and pharmacodynamic parameters, nomograms for bolus dose and
infusion rates at each age and LBM were derived. Three populations of 500 individuals each, ages 20, 50, and 80 yr, were
simulated base on the interindividual variances in model parameters as estimated by the NONMEM software package. The
peak EEG effect in response to a bolus, the steady-state EEG effect in response to an infusion, and the time course of drug
effect were examined in each of the three populations. Simulations were performed to examine the time necessary to
achieve a 20%, 50%, and 80% decrease in remifentanil effect site concentration after a variable-length infusion. The
variability in the time for a 50% decrease in effect site concentrations was examined in each of the three simulated
populations. Titratability using a constant-rate infusion was also examined.
Results: After a bolus dose, the age-related changes in V1 and ke0 nearly offset each other. The peak effect site
concentration reached after a bolus dose does not depend on age. However, the peak effect site concentration occurs later
in elderly individuals. Because the EEG shows increased brain sensitivity to opioids with increasing age, an 80-yr-old person
required approximately one half the bolus dose of a 20-yr old of similar LBM to reach the same peak EEG effect. Failure to
adjust the bolus dose for age resulted in a more rapid onset of EEG effect and prolonged duration of EEG effect in the
simulated elderly population. The infusion rate required to maintain 50% EEG effect in a typical 80-yr-old is approximately
one third that required in a typical 20-yr-old. Failure to adjust the infusion rate for age resulted in a more rapid onset of EEG
effect and more profound steady-state EEG effect in the simulated elderly population. The typical times required for
remifentanil effect site concentrations to decrease by 20%, 50%, and 80% after prolonged administration are rapid and little
affected by age or duration of infusion. These simulations suggest that the time required for a decrease in effect site
concentrations will be more variable in the elderly. As a result, elderly patients may occasionally have a slower emergence
from anesthesia than expected. A step change in the remifentanil infusion rate resulted in a rapid and predictable change of
EEG effect in both the young and the elderly.
Conclusions: Based
on the EEG model, age and LBM are significant
demographic factors that must be considered when determining a dosage
regimen for remifentanil. This remains true even when interindividual
pharmacokinetic and pharmacodynamic variability are incorporated in the
analysis.

129.
Kirkegaard-Nielsen H, Helbo-Hansen HS, Lindholm P, Severinsen IK,
Pedersen HS. Anthropometric variables as predictors for duration of
action of atracurium-induced neuromuscular block. Anesth Analg 1996;
83:1076-80.
•
Reports concerning duration of action of atracurium in obese patients are conflicting. The
aim of this study was to evaluate different anthropometric variables as predictors for
duration of action of atracurium-induced block. We studied 127 female patients (total body
weight 46–119 kg) anesthetized with midazolam, fentanyl, thiopental, nitrous oxide, and
halothane. Twelve different anthropometric variables were evaluated as predictors for
duration of action. Linear, least-square, regression analyses were used. There was a
significant correlation between each of the 12 variables and the duration of action. The
predictors with the greatest correlation coefficients for duration of action of the atracurium
induction dose (0.5 mg/kg) were total body weight divided by surface area (r2 = 0.284, P <
0.0001), body mass index (r2 = 0.265, P < 0.0001), and total body weight (r2 = 0.264, P <
0.0001). The most significant predictors for the duration of action of the first supplemental
atracurium dose (0.15 mg/kg) were total body weight divided by surface area (r2 = 0.170,
P < 0.0001) and total body weight (r2 = 0.160, P < 0.0001). We propose that the
atracurium dose should be reduced with 0.23 mg for each kilogram of total body weight
above 70 kg. We conclude that the duration of action of atracurium block is prolonged in
obese patients, and that atracurium dose in milligrams per kilogram of total body weight
should be reduced in these patients. Total body weight divided by the surface area and
total body weight were the best predictors for duration of action of atracurium-induced
neuromuscular block.

136.
Varin F, Ducharme J, Théorêt Y, et al. Influence of extreme obesity on
the body disposition and neuromuscular blocking effect of atracurium.
Clin Pharmacol Ther 1990; 48:18-25.
•
- The pharmacokinetics and pharmacodynamics of atracurium, a nondepolarizing
neuromuscular blocking agent, were compared between morbidly obese patients and
nonobese patients. Atracurium besylate (0.2 mg/kg) was administered intravenously as a
bolus to patients who had received anesthesia. The force of contraction of the adductor
pollicis was measured and plasma samples were collected for a 2-hour period. The
concentrations of atracurium and its major end product, laudanosine, were determined by use
of a chromatographic method. The pharmacokinetic-pharmacodynamic relationship was
characterized by use of several models. No difference was observed between obese patients
and nonobese patients in atracurium elimination half-life (19.8 +/- 0.7 versus 19.7 +/- 0.7
minutes), volume of distribution at steady state (8.6 +/- 0.7 versus 8.5 +/- 0.7 L), and total
clearance (444 +/- 29 versus 404 +/- 25 ml/min). However, if values were expressed on a
total body weight basis, there was a difference between obese and nonobese patients in the
volume of distribution at steady state (0.067 versus 0.141 L/kg) and total clearance (3.5 +/0.2 versus 6.6 +/- 0.5 ml/min/kg). Although atracurium concentrations were consistently
higher in obese patients than in nonobese patients, there was no difference in the time of
recovery from neuromuscular blockade between the two groups. Consequently, the median
effective concentration was higher in obese than in nonobese patients (470 +/- 46 versus 312
+/- 33 ng/ml).

145.
Cucuianu M, Popescu TA, Haragus S.
Pseudocholinesterase in obese and hyperlipemic
subjects.Clin Chim Acta. 1968 Oct;22(2):151-5
It was found that serum
pseudocholinesterase increases
not only in obese subjects but also in hyperlipemic
patients with normal body weight. A good statistical
correlation was found between serum pseudocholinesterase
on one hand, and both serum cholesterol and the logarithm of
serum triglycérides concentration, on the other. It cannot be
stated whether increased pseudocholinesterase activity should
be correlated with a possible role of the enzyme in the
metabolism of lipids or with an unspecific and rather general
stimulation of protein synthesis in the liver of obese and
hyperlipemic subjects.

146.
Kean KT, Kutty KM, Huang SN, Jain R.
A study of pseudocholinesterase induction in experimental
obesity.J Am Coll Nutr. 1986;5(3):253-61
Liver pseudocholinesterase (PChE) activity was significantly
higher in genetically obese (ob/ob) mice than in lean
littermates as early as 23 days after birth. By cytochemical
electron microscopy, increased staining for PChE was
observed in the rough endoplasmic reticulum of ob/ob mice.
Albino mice with different diets showed that high-protein diets
produced the greatest increase in PChE activity in the liver
compared to carbohydrate or high fat. Mice fed a normal
mouse diet ad lib had significantly higher liver PChE activity
than those fed a restricted diet of 2 g of a normal mouse chow
per day. In albino mice liver PChE activity varied directly with
the protein content in the diet. These studies suggest that
liver PChE induction is a function of the level of
protein in the diet.

147.
Rose JB,Theroux MC,Katz M S.The Potency of
Succinylcholine in Obese Adolescents. Anesth
Analg 2000; 90:576–8
•
•
ABSTRACT: We constructed a single-dose response curve for succinylcholine in 30
obese adolescents during thiopental-fentanyl anesthesia administration by using 100
mg/kg, 150 mg/kg, or 250 mg/kg IV. The maximal response (percent depression of
neuromuscular function) of the adductor pollicis to supramaximal train-of-four stimuli
was recorded by using a Datex (Helsinki, Finland) relaxograph. Linear regression and
inverse prediction were used to determine doses of succinylcholine to produce 50%
(ED50), 90% (ED90), and 95% (ED95) depression of neuromuscular function. The
ED50, ED90, and ED95 were 152.8 mg/kg (95% confidence interval: 77.8–299.5),
275.4 mg/kg (95% confidence interval: 142–545.7), and 344.3 mg/kg (95%
confidence interval: 175.3–675.3), respectively. This ED50 is similar to the dose
reported for similarly aged, nonobese adolescents, 147 mg/kg. The previously
reported ED95 for succinylcholine in nonobese adolescents, 270 mg/kg, is within the
95% confidence interval generated for ED95 in our study. Implications: The potency
estimates for succinylcholine in obese (body mass index > 30 kg/m2) adolescents are
comparable to those in similarly aged nonobese adolescents when dosing is
calculated based on total body mass and not lean body mass. When a rapid
sequence induction of anesthesia is considered in an obese adolescent, the dose of
succinylcholine should be based on actual (not lean) body mass.

148.
Rose JB,Theroux MC,Katz M S.The Potency of Succinylcholine in Obese
Adolescents. Anesth Analg 2000; 90:576–8.
• ED50, ED90, and ED95 with lower and upper 95%
confidence intervals in microg/kg are 152.8 (77.8 and
299.5), 275.4 (142 and 545.7), and 344.3 (175.3 and
675.3), respectively
• the potency of SCH in obese adolescents, as estimated
by the ED50 of 158 mg/kg, is similar to the value of 147
mg/kg reported previously for lean adolescents
• . The ED95 of SCH in lean adolescents, 270 mg/kg,
occurs within the 95% confidence intervals generated for
obese adolescents in the present study .
• Of further interest is our finding that PCHE levels may
be increased in obese adolescents. We have no
explanation for this observation; however, similar results
have been noted in studies of obese adults

164.
Kapila A, Glass PSA, Jacobs JR, Muir KT, Hermann
DJ, Shiraishi M, Howell S, Smith RL: Measured
context-sensitive half-times of remifentanil and
alfentanil. ANESTHESIOLOGY 83:968-75, 1995
•
BACKGROUND: The context-sensitive half-time, rather than the terminal elimination halflife, has been proposed as a more clinically relevant measure of decreasing drug
concentration after a constant infusion of a given duration. The context-sensitive half-time is
derived from computer modelling using known pharmacokinetic parameters. The modelled
context-sensitive half-time for a 3-h infusion of alfentanil is 50-55 min and is 3 min for
remifentanil. The terminal elimination half-life is 111 min for alfentanil and 12-30 min for
remifentanil. It has not been tested whether the modelled context-sensitive half-time reflects
the true time for a 50% decrease in drug concentration or drug effect. METHODS: Thirty
volunteers received a 3-h infusion of remifentanil or alfentanil at equieffective
concentrations. Depression of minute ventilation to 7.5% ETCO2 was used as a measure of
drug effect. Minute ventilation response was measured, and blood samples for drug
concentration were taken during and after drug infusion. The recovery of minute ventilation
(drug effect) and decrease in blood drug concentration was plotted, and the time for a 50%
change was determined. RESULTS: The measured pharmacokinetic context-sensitive halftime for remifentanil after a 3-h infusion was 3.2 +/- 0.9 min, and its pharmacodynamic offset
was 5.4 +/- 1.8 min. Alfentanil's measured pharmacokinetic context-sensitive half-time was
47.3 +/- 12 min, and its pharmacodynamic offset was 54.0 +/- 48 min. The terminal
elimination half-life modelled from the volunteers was 11.8 +/- 5.1 min for remifentanil and
76.5 +/- 12.6 min for alfentanil. CONCLUSIONS: The measured context-sensitive half-times
were in close agreement with the context-sensitive half-times previously modelled for these
drugs. The results of this study confirm the value of the context-sensitive half-time in
describing drug offset compared to the terminal elimination half-life.

165.
Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic
interaction between propofol and remifentanil regarding
hypnosis,tolerance of laryngoscopy, bispectral index, and
electroencephalographic approximate entropy.
Anesthesiology. 2004;100:1353-1372.
•
•
•
•
Background: The purpose of this investigation was to describe the pharmacodynamic interaction
between propofol and remifentanil for probability of no response to shaking and shouting, probability of
no response to laryngoscopy, Bispectral Index (BIS), and electroencephalographic approximate
entropy (AE).
Methods: Twenty healthy volunteers received either propofol or remifentanil alone and then
concurrently with a fixed concentration of remifentanil or propofol, respectively, via a target-controlled
infusion. Responses to shaking and shouting and to laryngoscopy were assessed multiple times after
allowing for plasma effect site equilibration. The raw electroencephalogram and BIS were recorded
throughout the study, and AE was calculated off-line. Response surfaces were fit to the clinical
response data using logistic regression or hierarchical response models. Response surfaces were also
estimated for BIS and AE. Surfaces were visualized using three-dimensional rotations. Model
parameters were estimated with NONMEM.
Results: Remifentanil alone had no appreciable effect on response to shaking and shouting or
response to laryngoscopy. Propofol could ablate both responses. Modest remifentanil concentrations
dramatically reduced the concentrations of propofol required to ablate both responses. The hierarchical
response surface described the data better than empirical logistic regression. BIS and AE are more
sensitive to propofol than to remifentanil.
Conclusions: Remifentanil alone is ineffective at ablating response to stimuli but demonstrates
potent synergy with propofol. BIS and AE values corresponding to 95% probability of ablating response
are influenced by the combination of propofol and remifentanil to achieve this endpoint, with higher
propofol concentrations producing lower values for BIS and AE.

176.
Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic
interaction between propofol and remifentanil regarding hypnosis,tolerance of
laryngoscopy, bispectral index, and
electroencephalographic approximate entropy. Anesthesiology. 2004;100:13531372.
•
•
•
•
•
•
•
•
This investigation was intended to quantify interaction between propofol and remifentanil on
ablating response to a primarily hypnotic endpoint, loss of response to shaking and shouting, and
a hypnotic—analgesic endpoint, the loss of response to laryngoscopy, while concurrently
quantifying the interaction of propofol and remifentanil on two electroencephalographic measures
of drug effect, BIS and AE. The major results are as follows:
1. The interaction between propofol and remifentanil is synergistic for loss of response to shaking
and shouting and for loss of response to laryngoscopy.
2. Remifentanil is not hypnotic in clinically relevant concentrations.
3. Remifentanil concentrations of 4 ng/ml reduce the propofol concentration associated with loss
of response to shaking and shouting and to laryngoscopy by approximately two thirds. Further
increases in remifentanil only modestly reduce the propofol concentration required to ablate the
response to either stimulus.
4. Propofol was equipotent in its effect on BIS and AE, with or without remifentanil.
5. The interaction between propofol and remifentanil on BIS and AE was additive, but in the
clinical range (< 8 ng/ml), remifentanil had little effect on either electroencephalographic measure
of drug effect.
6. The combination of propofol and remifentanil chosen to ablate response has a large effect on
the concurrent electroencephalographic measure of drug effect.
7. The new hierarchical model provides a better prediction of the likelihood of response than the
empirical model described by Minto.

177.
Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic
interaction between propofol and remifentanil regarding hypnosis,tolerance of
laryngoscopy, bispectral index, and
electroencephalographic approximate entropy. Anesthesiology. 2004;100:13531372.
•
•
•
•
•
•
•
Clinical Assessment of Propofol—Remifentanil Interaction
The synergy between opioids and propofol is well established. In this light, our findings of a synergistic interaction on loss of response to shaking and shouting and
loss of response to laryngoscopy are hardly surprising. Only two other studies specifically investigating the interaction between propofol and remifentanil with regard to
clinical endpoints are available for comparison. Roepcke et al. investigated the interaction of propofol and remifentanil to maintain a BIS between 45 and 55 during
orthopedic surgical procedures. Propofol was administered with a TCI device at predetermined concentrations between 1.5 and 6 mg/ml and supplemented with the
corresponding remifentanil concentration via TCI to maintain the target BIS. The data were analyzed with an isobolographic analysis, and a synergistic interaction was
found similar to that reported here. Mertens et al. investigated the interaction of propofol and remifentanil on tolerance of laryngoscopy, intubation, adequate anesthesia,
and awakening. They concluded that the interaction is synergistic, but additive in the clinical range. Their results for loss of response to laryngoscopy are similar to ours.
In their study, the C50 of propofol for tolerance to laryngoscopy decreased was 6 mg/ml in absence of remifentanil, which decreased to 2 mg/ml when the remifentanil
concentration was 3.4 ng/ml. Our corresponding results are 6.62 mg/ml propofol (TCI predictions) in the absence of remifentanil and 2 mg/ml propofol at a remifentanil
target concentration of 3.5 ng/ml. As judged from , the interaction between remifentanil and propofol, although synergistic over the entire range of propofol
concentrations, may seem additive for propofol concentrations between 2 and 6 mg/ml propofol, and thus, the findings reported by Mertens et al. are consistent with our
results.
Our estimates of the C50 of propofol alone for attenuation of response to noxious stimulation are less than some previously reported estimates. For example, Kazama
et al. estimated that the C50 to blunt response to laryngoscopy was 9.8 mg/ml, which was confirmed as being 10.9 mg/ml in a subsequent study by the same authors. As
reported by Kazama et al. and by Zbinden et al., the C50 for laryngoscopy is similar for that to incision. Therefore, it is also relevant that Smith et al. reported that the C50
of propofol for skin incision in the absence of opioids was 15.2 mg/ml. In contrast, our values for the C50 of propofol to ablate response to laryngoscopy range from a low
of 3.2 mg/ml () to a high of 8.44 mg/ml (, C50 propofol ´ preopioid stimulus for the model using TCI concentrations). We do not have a ready explanation for this
discrepancy. It could relate to laryngoscopic technique, but we were able to visualize vocal cords in every laryngoscopy, so in our view, the technique was adequately
vigorous. Nevertheless, the data suggest that our laryngoscopy technique was less stimulating than that of other investigators, resulting in a lower estimate of the C50 of
propofol.
The hypnotic properties of remifentanil and other opioids have been investigated. Jhaveri et al. concluded that the median effective concentration of remifentanil for
loss of consciousness equals 54 ng/ml, and therefore, remifentanil is not suitable as a sole induction agent. We calculated the C50 of remifentanil at approximately 19
ng/ml, much lower, but still clearly outside the clinically used range. This agrees with the findings of Vuyk et al. as well, who concluded that alfentanil was not suitable as
a sole induction agent.
Although remifentanil is not a hypnotic in the clinically relevant concentration range, it profoundly decreases the propofol concentration for loss of response to shaking
and shouting. Without remifentanil, 8.6 mg/ml propofol is needed to ablate response to shaking and shouting in 95% of patients (hierarchical model, TCI concentrations,
calculated from ). This is reduced to only 0.88 mg/ml in presence of 6 ng/ml remifentanil, a concentration of remifentanil that does not cause unconsciousness during
monoadministration. A similar relation exists with regard to laryngoscopy. In the absence of remifentanil, 15 mg/ml propofol is needed to ensure a 95% probability of no
response to laryngoscopy. In presence of 6 ng/ml remifentanil, the propofol concentration associated with 95% probability of no response decreases to 2.5 mg/ml. These
data is similar to data from interaction studies between propofol and fentanyl (corrected for relative potency of the fentanyl), as well as isoflurane and remifentanil.
The SEs of the parameter estimates for the Minto empirical model with TCI concentrations were modest (), suggesting that there was enough data relative to the
numbers of parameters in the model to estimate the parameters accurately. However, we found that our data set was very sensitive to initial estimates. Some initial
estimates produced reasonable estimates of SEs but had objective functions approximately 10 points higher than those in and . When we used starting estimates that
produced the best fits, as determined from the objective function, the estimates of SEs became exceedingly small. Our guess is that the small SEs are NONMEM's
representation of the same dependence on starting estimates, in that very small changes in the estimates produce significantly worse fits, thus leading to very small SEs.
We also note that the coefficient variations on most of the parameters in and are reasonable. This means that although the subjects differ from each other, the
response of the typical patient (e.g., and ) is a useful starting point for titration. We also note the high coefficient variation values (about 100%) for the estimates of the
steepness of the propofol concentration—versus—probability of no response relation with the hierarchical model. When the slopes become quite steep (e.g., 5 and 7 for
the TCI and Bayesian models, respectively), they can vary considerably without being clinically distinguishable.

178.
Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic
interaction between propofol and remifentanil regarding hypnosis,tolerance of
laryngoscopy, bispectral index, and
electroencephalographic approximate entropy. Anesthesiology. 2004;100:13531372.
•
•
•
•
•
Choice of Models for Clinical Assessment
The parameters for the hierarchical model are interesting in comparison with those of the Minto empirical model.
First, the C50 of remifentanil has been reduced from approximately 19 in the empirical model () to approximately 1
ng/ml in the hierarchical model (). This is because the model estimates something that remifentanil can do: attenuate
the intensity of noxious stimulation, rather than something remifentanil cannot do: prevent response to noxious
stimulation. The model thus directly reports the “take home” message: Only a modest amount of remifentanil is
required to blunt response to noxious stimulation. Our estimate that 1 ng/ml remifentanil reduces the propofol dose by
50% is similar to the estimate of Lang et al. that the minimum alveolar concentration (MAC) of isoflurane is 50%
reduced by a remifentanil concentration of 1.37 ng/ml.
The model also estimates a steepness parameter for remifentanil slightly less than 1. This indicates that increasing
the opioid beyond the C50 does continue to produce increased opioid drug effect but that the incremental benefit
relative to the increase in concentration is modest. This is exactly the message from careful analysis of the empirical
model as well, but it does not emerge from simple analysis of the parameters of the empirical model ().
The C50 values for propofol in the hierarchical model are higher than those estimated with the Minto model. For the
hierarchical model, the propofol C50s are, by definition, the hypnotic concentration associated with 50% probability of
no response when the preopioid stimulus intensity equals 1 and no opioid is present. This is approximately the level
of intensity of stimulation associated with laryngoscopy. The propofol C50 for hypnosis in the absence of opioids is
the C50 value times the prestimulus intensity of shaking and shouting, which is approximately 0.5. This can be seen in
the bottom two graphs of , which are the propofol concentration—versus—probability of no response curves for
hypnosis (left) and laryngoscopy (right) in the absence of opioid.
It is interesting that the “preopioid stimulus,” the only parameter that differs between the model for no response to
shouting and shaking, and the model for no response to laryngoscopy suggest that the level of arousal associated
with shaking and shouting is 0.5, whereas the level associated with laryngoscopy is 1.0. We speculated that perhaps
this parameter could be set arbitrarily to 1.0 for the first model and could thus be interpreted as “stimulation level
relative to shaking and shouting.” However, this significantly reduced the NONMEM objective function, indicating that
this parameter cannot arbitrarily be set to one for a particular stimulus-response pair. We have two possible
explanations for why the preopioid stimulus for shaking and shouting is half of that for laryngoscopy, rather than, say,
a tenth. One possibility is that the baseline stimulus of simply being alive is only slightly less than 0.5, and thus,
shaking and shouting is adding only slightly to the baseline stimulus level (e.g., baseline = 0.4, shaking and shouting =
+0.1), while laryngoscopy adds several-fold more input (e.g., +0.5). Alternatively, shouting and shaking as practiced by
the assessor (S. L. S.) may have been quite noxious and thus benefited from the analgesic properties of remifentanil.
This is the first introduction of the hierarchical model. We expect that as experience with this model grows, it will
become clearer how to interpret the preopioid stimulus estimated by the model. The model could be expanded by
adding another input for strictly hypnotic drug effect to equation 4:

179.
•
•
•
•
Electroencephalographic Assessment of Propofol—Remifentanil Interaction
The C50 of propofol for reduction of the BIS was almost identical to that for AE with both monoadministration and the
propofol—remifentanil interaction model, indicating that both measurements are nearly interchangeable measures of propofol
drug effect. The C50 values for both propofol and remifentanil are in good agreement with those published previously.
Initial studies of the BIS showed that it worked well when propofol was the primary anesthetic agent but did not work well for
anesthetics that combined nitrous oxide with high-dose opioids. For this reason, we integrated the synergistic response surface
of the hierarchical model with the additive response surface of the electroencephalographic model to explore the influence of
the anesthetic combination on the electroencephalographic measure of drug effect. The results ( and ) show that
electroencephalographic measures alone are not adequate to predict the probability of response but must be interpreted in light
of the drug concentration used to achieve the electroencephalographic response. For example, at 16 ng/ml remifentanil and
0.11 mg/ml propofol, the probability of response to shouting and shaking is 95%, but the calculated BIS is 54 (). However, at a
remifentanil concentration of 4 ng/ml and a propofol concentration of 1.25 mg/ml, the probability of no response to shouting and
shaking is 95%, and the calculated BIS is 72. Similarly, at a propofol concentration of 4.7 mg/ml, in the absence of remifentanil,
there is a 95% chance of response to laryngoscopy (), even though the calculated BIS is 46. However, at a propofol
concentration of 2.5 mg/ml and a remifentanil concentration of 6 ng/ml, there is a 95% chance of no response, and the
calculated BIS is 54. This analysis emphasizes that BIS (and, presumably, most other electroencephalographic measures used
to assess anesthetic depth) are measures of hypnotic drug effect, and the brain's response to both the drugs and the surgical
stimulus and are not measures of the brain's likelihood of response to noxious stimulation. Because electroencephalographic
response does not measure an intrinsic state of the brain, interpretation of electroencephalographic measures requires
consideration of the drugs used.
In summary, response surface methodology has demonstrated that propofol and remifentanil are synergistic for the clinical
endpoints of no response to shouting and shaking and no response to laryngoscopy and have additive effects on two
electroencephalographic measures of drug effect, the BIS and AE. This should caution the reader against using BIS or other
measurements of anesthetic depth without considering the relative contributions of a hypnotic and an opioid to the anesthetic
state. These models may have applicability in designing anesthetic regimens and closed-loop control of anesthesia
administering both an opioid and a hypnotic using electroencephalographic measures of drug effect.

180.
Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk J.Propofol
Reduces Perioperative Remifentanil Requirements in a Synergistic
Manner. Response Surface Modeling of Perioperative Remifentanil—
Propofol Interactions Anesthesiology, 99:347-59, 2003
•
•
•
•
•
•
•
•
•
* Staff Anesthesiologist, † Research Associate, ‡ Professor of Anesthesiology and Head of the Anesthesia Research Laboratory, §
Professor of Anesthesiology.
Received from the Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands. Submitted for
publication December 3, 2001. Accepted for publication April 1, 2003. Supported by GlaxoSmithKline BV, Zeist, The Netherlands.
Presented in part at the annual meeting of the European Society of Anaesthesiologists, in Gothenburg, Sweden, October 4, 2001.
Address reprint requests to Dr. Mertens: Department of Anesthesiology, Leiden University Medical Center, PO Box 9600, 2300 RC,
Leiden, The Netherlands. Address electronic mail to: m.j.mertens@lumc.nl. Individual article reprints may be purchased through the
Journal Web site, www.anesthesiology.org.
ABSTRACT:
Background: Remifentanil is often combined with propofol for induction and maintenance of total intravenous anesthesia.
The authors studied the effect of propofol on remifentanil requirements for suppression of responses to clinically relevant stimuli and
evaluated this in relation to previously published data on propofol and alfentanil.
Methods: With ethics committee approval and informed consent, 30 unpremedicated female patients with American Society of
Anesthesiologists physical status class I or II, aged 18–65 yr, scheduled to undergo lower abdominal surgery, were randomly assigned to
receive a target-controlled infusion of propofol with constant target concentrations of 2, 4, or 6 mg/ml. The target concentration of
remifentanil was changed in response to signs of inadequate anesthesia. Arterial blood samples for the determination of remifentanil and
propofol concentrations were collected after blood—effect site equilibration. The presence or absence of responses to various
perioperative stimuli were related to the propofol and remifentanil concentrations by response surface modeling or logistic regression,
followed by regression analysis. Both additive and nonadditive interaction models were explored.
Results: With blood propofol concentrations increasing from 2 to 7.3 mg/ml, the C50 of remifentanil decreased from 3.8 ng/ml to 0
ng/ml for laryngoscopy, from 4.4 ng/ml to 1.2 ng/ml for intubation, and from 6.3 ng/ml to 0.4 ng/ml for intraabdominal surgery. With blood
remifentanil concentrations increasing from 0 to 7 ng/ml, the C50 of propofol for the return to consciousness decreased from 3.5 mg/ml to
0.6 mg/ml.
Conclusions: Propofol reduces remifentanil requirements for suppression of responses to laryngoscopy, intubation, and intraabdominal
surgical stimulation in a synergistic manner. In addition, remifentanil decreases propofol concentrations associated with the return of
consciousness in a synergistic manner.

181.
Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk
J.Propofol Reduces Perioperative Remifentanil Requirements in a
Synergistic Manner. Response Surface Modeling of Perioperative
Remifentanil—Propofol Interactions Anesthesiology, 99:347-59,
2003
•
•
•
The C50 of remifentanil for laryngoscopy and intubation decreased with increasing propofol concentrations. For laryngoscopy and
intubation, the data were best characterized by a synergistic model (). The addition of the interaction term in the response surface model
resulted in a reduction in the AIC (from 62.41 to 59.51 for laryngoscopy and from 39.21 to 34.95 for intubation). Introduction of
intraindividual variability did not result in a further reduction in the AIC. As blood propofol concentrations increased from 2 to 7.3 mg/ml,
the C50 of remifentanil decreased from 3.8 ng/ml to 0 ng/ml for laryngoscopy and from 4.7 ng/ml to 1.2 ng/ml for intubation ( and ). For
skin incision and the opening of the peritoneum, the configuration of the data did not allow modeling.
In 3 of 29 patients, the data set for intraoperative stimuli did not allow modeling. The concentration—effect relation of remifentanil for
intraabdominal stimuli could therefore not be determined in these 3 patients. In 17 patients, no overlap existed between response and
nonresponse data. Because the lowest measured plasma remifentanil concentration at which no response occurred and the highest blood
remifentanil concentration at which a response was noted differed only marginally in these patients, the C50 of remifentanil was
determined as the midrange between the lowest measured blood remifentanil concentration at which no response occurred and the
highest blood remifentanil concentration at which a response was noted. If in any patient no responses occurred, even when the actual
measured blood remifentanil concentration was below the detection limit, the C50 of remifentanil was set to 0 ng/ml. The measured blood
propofol concentration remained stable throughout the surgical procedure in most patients (). The remifentanil concentration—effect
relations for the intraabdominal part of the surgical procedure in the individual patients of the three groups are shown in , , . Results are
presented in . The C50 of remifentanil versus mean blood propofol concentration relation for the intraabdominal part of surgery as
determined over all patients is presented in . The C50 of remifentanil for suppression of responses to intraabdominal surgical stimuli
decreased with increasing propofol concentrations. The data were best characterized by a synergistic model. The addition of the
interaction term in the model resulted in a reduction in the AIC from 82.07 to 79.96. Because C50,rem and Î of the nonadditive model
were very large, the model described in equation 9 was fitted to the data. The parameters (± SE) describing the curve are C50,prop =
9.02 ± 2.47 mg/ml and Î¢ = 0.557 ± 0.306. Introduction of intraindividual variability did not result in a further reduction in the AIC. As mean
blood propofol concentrations increased from 2 to 9 mg/ml, the C50 of remifentanil for intraabdominal stimuli decreased from 6.3 to 0
ng/ml ().
Remifentanil significantly affected the blood propofol concentration at which the patients regained consciousness. According to the
response surface modeling technique described by Bol et al., the interaction between propofol and remifentanil was judged to be
synergistic for the probability of unconsciousness (). Introduction of intraindividual variability did not result in a further reduction in the AIC.
With blood remifentanil concentration increasing from 0 to 10 ng/ml, the C50,prop for return of to consciousness decreased from 3.5
mg/ml to 0.4 mg/ml (). For this unimodal end point, the response surface modeling technique described by Minto et al. proved also
adequate. The additive model with the lowest AIC is a model in which gprop and grem are identical. Introduction of intraindividual
variability did not result in a further reduction in the AIC. Because the addition of the interaction term b2,U50 (see Appendix) in the model
resulted in a reduction in the AIC from 48.152 to 46.409, the interaction between propofol and remifentanil for the probability of
unconsciousness based on the response surface modeling technique described by Minto et al. was also judged synergistic. The
parameters (± SE) describing the response surface are E0 = 0, Emax = 1, C50,prop = 3.40 ± 0.75 mg/ml, C50,rem = 8.91 ± 2.35 ng/ml,
gprop = 4.29 ± 0.98, grem = 4.29 ± 0.98, and b2,U50 = 1.69 ± 0.42. The C50 of propofol decreased from 3.4 mg/ml to 0.5 mg/ml as blood
remifentanil concentrations increased from 0 to 8 ng/ml. The model described in equation 2 was selected as the final model for the return
to consciousness because its AIC was lower than that for the model described by

184.
Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk
J.Propofol Reduces Perioperative Remifentanil Requirements in a
Synergistic Manner. Response Surface Modeling of Perioperative
Remifentanil—Propofol Interactions Anesthesiology, 99:347-59,
2003
•
•
•
Laryngoscopy and Intubation
In keeping with the observations of Vuyk et al. on the interactions between propofol
and alfentanil, the interactions between propofol and remifentanil for suppression of
responses to laryngoscopy and intubation were best described by a synergistic
interaction model. For laryngoscopy, the C50,rem and Î estimated with the model
described by Bol et al. were very large, whereas for intubation, C50,rem, C50,prop,
and Î were several orders of magnitude larger than the concentrations encountered in
this study. Therefore, these effects were modeled with the modified models
(equations 2 and 3, respectively). Similarly, Vuyk et al. have demonstrated that
propofol decreases alfentanil requirements for suppression of responses to
laryngoscopy and intubation in a synergistic manner.
Remifentanil concentrations required to suppress responses to intubation are
higher at any given propofol concentration compared to those required to suppress
responses to laryngoscopy. This indicates that tracheal intubation is a stronger
stimulus than laryngoscopy. The C50 of propofol for laryngoscopy in the absence of
remifentanil, determined as the intercept of the interaction model with the x-axis (), is
7.3 mg/ml. Because the interaction model for suppression of responses to intubation
did not cross the x-axis in the concentration range studied (), the C50 of propofol
alone for intubation could not be determined. These findings are in accordance with
the findings of Kazama et al., who determined the C50s of propofol for laryngoscopy
and intubation at 9.8 and 17.4 mg/ml, respectively.

185.
Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk
J.Propofol Reduces Perioperative Remifentanil Requirements in a
Synergistic Manner. Response Surface Modeling of Perioperative
Remifentanil—Propofol Interactions Anesthesiology, 99:347-59,
2003
• Return of Consciousness
•
The propofol C50 for return of consciousness of 3.5 mg/ml
corresponds well with the reported propofol concentrations at which
consciousness was lost in 50% of the patients of 3.4 mg/ml.
However, the C50,prop for return of consciousness determined in
our study is lower than the C50,prop for return of consciousness of
approximately 4 mg/ml determined in a similar study after total
intravenous anesthesia with propofol and alfentanil. It is conceivable
that 0.2 mg/kg morphine administered 30 min before the end of
surgery to provide adequate initial postoperative pain control after
remifentanil anesthesia may have lowered the concentration at
which patients regained consciousness and delayed the return of
consciousness in our study group.

189.
Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk
J.Propofol Reduces Perioperative Remifentanil Requirements in a
Synergistic Manner. Response Surface Modeling of Perioperative
Remifentanil—Propofol Interactions Anesthesiology, 99:347-59,
2003
•
•
Based on the results of this study and our clinical experience, we recommend a
minimum effect site propofol concentration of 2.0 mg/ml in combination with an effect
site remifentanil concentration of 6.3 ng/ml in female patients with American Society
of Anesthesiologists physical status I or II in the absence of premedication and
significant muscle relaxation. These “optimal” effect site concentrations can be used
as guidelines during target-controlled infusion. The actual target concentrations
during anesthesia will have to be titrated to the desired effect. Dosing guidelines to
rapidly achieve these adequate effect site concentrations without target controlled
infusion are given in .
A “low” target propofol concentration of 2.0 mg/ml in combination with a relatively
higher remifentanil concentration of 6.3 ng/ml should only be used in the absence of
significant muscle relaxation. When maximum muscle relaxation is required for
surgery, we advise use of a target propofol concentration of 3 mg/ml or greater to
reduce the risk of awareness. To avoid unrecognized awareness, premedication will
further increase the margin of safety. None of the patients in our study had recall of
any perioperative event. Patients in group A (the lowest target propofol concentration
of 2.0 mg/ml) were hemodynamically stable, and the mean intraoperative Bispectral
Index value was 59 (). Because the level of intraoperative neuromuscular blockade
was maintained at a train-of-four level of 1–3, patients were able to move in response
to inadequate anesthesia at all times.